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Title: MicroRNAs form triplexes with double stranded DNA at sequence-specific binding sites; a eukaryotic mechanism via which microRNAs could directly alter gene expression

MicroRNAs are important regulators of gene expression, acting primarily by binding to sequence-specific locations on already transcribed messenger RNAs (mRNA). Recent studies indicate that microRNAs may also play a role in up-regulating mRNA transcription levels, although a definitive mechanism has not been established. Double-helical DNA is capable of forming triple-helical structures through Hoogsteen and reverse Hoogsteen interactions in the major groove of the duplex, and we show physical evidence that microRNAs form triple-helical structures with duplex DNA, and identify microRNA sequences that favor triplex formation. We developed an algorithm (Trident) to search genome-wide for potential triplex-forming sites and show that several mammalian and non-mammalian genomes are enriched for strong microRNA triplex binding sites. We show that those genes containing sequences favoring microRNA triplex formation are markedly enriched (3.3 fold, p<2.2 x 10 -16) for genes whose expression is positively correlated with expression of microRNAs targeting triplex binding sequences. As a result, this work has thus revealed a new mechanism by which microRNAs can interact with gene promoter regions to modify gene transcription.
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [1] ;  [1]
  1. St. Jude Children's Research Hospital, Memphis, TN (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Univ. of Oxford, Oxford (United Kingdom)
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 12; Journal Issue: 2; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; microRNAs; DNA structure; DNA; electrophoretic mobility shift assay; purines; gene expression; DNA methylation; RNA stem-loop structure
OSTI Identifier:
1263831

Paugh, Steven W., Coss, David R., Bao, Ju, Laudermilk, Lucas T., Grace, Christy R., Ferreira, Antonio M., Waddell, M. Brett, Ridout, Granger, Naeve, Deanna, Leuze, Michael Rex, LoCascio, Philip F., Panetta, John C., Wilkinson, Mark R., Pui, Ching -Hon, Naeve, Clayton W., Uberbacher, Edward C., Bonten, Erik J., and Evans, William E.. MicroRNAs form triplexes with double stranded DNA at sequence-specific binding sites; a eukaryotic mechanism via which microRNAs could directly alter gene expression. United States: N. p., Web. doi:10.1371/journal.pcbi.1004744.
Paugh, Steven W., Coss, David R., Bao, Ju, Laudermilk, Lucas T., Grace, Christy R., Ferreira, Antonio M., Waddell, M. Brett, Ridout, Granger, Naeve, Deanna, Leuze, Michael Rex, LoCascio, Philip F., Panetta, John C., Wilkinson, Mark R., Pui, Ching -Hon, Naeve, Clayton W., Uberbacher, Edward C., Bonten, Erik J., & Evans, William E.. MicroRNAs form triplexes with double stranded DNA at sequence-specific binding sites; a eukaryotic mechanism via which microRNAs could directly alter gene expression. United States. doi:10.1371/journal.pcbi.1004744.
Paugh, Steven W., Coss, David R., Bao, Ju, Laudermilk, Lucas T., Grace, Christy R., Ferreira, Antonio M., Waddell, M. Brett, Ridout, Granger, Naeve, Deanna, Leuze, Michael Rex, LoCascio, Philip F., Panetta, John C., Wilkinson, Mark R., Pui, Ching -Hon, Naeve, Clayton W., Uberbacher, Edward C., Bonten, Erik J., and Evans, William E.. 2016. "MicroRNAs form triplexes with double stranded DNA at sequence-specific binding sites; a eukaryotic mechanism via which microRNAs could directly alter gene expression". United States. doi:10.1371/journal.pcbi.1004744. https://www.osti.gov/servlets/purl/1263831.
@article{osti_1263831,
title = {MicroRNAs form triplexes with double stranded DNA at sequence-specific binding sites; a eukaryotic mechanism via which microRNAs could directly alter gene expression},
author = {Paugh, Steven W. and Coss, David R. and Bao, Ju and Laudermilk, Lucas T. and Grace, Christy R. and Ferreira, Antonio M. and Waddell, M. Brett and Ridout, Granger and Naeve, Deanna and Leuze, Michael Rex and LoCascio, Philip F. and Panetta, John C. and Wilkinson, Mark R. and Pui, Ching -Hon and Naeve, Clayton W. and Uberbacher, Edward C. and Bonten, Erik J. and Evans, William E.},
abstractNote = {MicroRNAs are important regulators of gene expression, acting primarily by binding to sequence-specific locations on already transcribed messenger RNAs (mRNA). Recent studies indicate that microRNAs may also play a role in up-regulating mRNA transcription levels, although a definitive mechanism has not been established. Double-helical DNA is capable of forming triple-helical structures through Hoogsteen and reverse Hoogsteen interactions in the major groove of the duplex, and we show physical evidence that microRNAs form triple-helical structures with duplex DNA, and identify microRNA sequences that favor triplex formation. We developed an algorithm (Trident) to search genome-wide for potential triplex-forming sites and show that several mammalian and non-mammalian genomes are enriched for strong microRNA triplex binding sites. We show that those genes containing sequences favoring microRNA triplex formation are markedly enriched (3.3 fold, p<2.2 x 10-16) for genes whose expression is positively correlated with expression of microRNAs targeting triplex binding sequences. As a result, this work has thus revealed a new mechanism by which microRNAs can interact with gene promoter regions to modify gene transcription.},
doi = {10.1371/journal.pcbi.1004744},
journal = {PLoS Computational Biology (Online)},
number = 2,
volume = 12,
place = {United States},
year = {2016},
month = {2}
}